3,6-Dioxo-1,4-cyclohexadien-1-yl-butandate esters

ABSTRACT

A process for inversion of the stereo configuration of (R)-(+)-3,4-dihydro-6-hydroxy-2,5,7,8-tetraalkyl-2H-1-benzopyran-2-carboxylic acid and derivatives thereof to form the corresponding S-(-) acid and intermediates in this process.

BACKGROUND OF INVENTION

U.S. Pat. No. 3,947,473, Scott et al., discloses a compound ##STR1##wherein R₁, R₁ ', and R₁ " are independently hydrogen or lower alkyl,and R₂ is lower alkyl

And a method for resolving this compound into its two isomeric forms,i.e. ##STR2## wherein R₁, R₁ ', R₁ " are R₂ are as above. In many cases,it is desired to utilize the compound of formula I in its 2S form, i.e.the compound of formula I-B. This is especially true where R₁, R₁ ', R₁" and R₂ are methyl since this compound is an intermediate for naturaloptically active alpha-tocopherol, i.e. alpha tocopherol having the2R,4'R and 8'R configuration. Therefore, the compound of formula I-A maybe the undesired isomer and the conversion to the optically pure 2S formbe desired.

SUMMARY OF INVENTION

In accordance with this invention, it has been discovered that theoptically pure 2R compounds of formula I-A can be inverted to form theoptically pure 2S-isomer. Therefore, this invention provides a methodfor utilizing the unwanted 2R-isomer forproducing(2R,4'R,8'R)alpha-tocopherol. In this manner, both the isomersof formula I can be used, thereby improving the economy of the overallsynthesis of (2R,4'R,8'R)-α-tocopherol (natural Vitamin E). Further, itprovides a method for forming the antioxidants of formula I in theiroptically active 2S-configuration with an improved economy.

DETAILED DESCRIPTION

In the structural formula given throughout this application, thesubstituents attached to the molecule above the plane of the moleculeare designated by and the substituents attached to the molecule belowthe plane of the molecule are designated by . The numbering of thechromane ring in the compound of formula I is given for the purpose ofconvenience.

As used herein, the term lower alkyl designates straight and branchedchain aliphatic saturated hydrocarbon groups containing from 1 to 7carbon atoms such as methyl, ethyl, n-propyl, isopropyl, tert-butyl,isobutyl, etc. The term halogen includes all four halogens, i.e.chlorine, bromine, fluorine and iodine.

The compounds of formula I-A are converted to the compound of formulaI-B via the following intermediates: ##STR3## wherein R₁, R₁ ', R₁ " andR₂ are as above, and R₃ is lower alkyl, and R₄ is lower alkyl.

In accordance with this invention, the compound of formula I-A isinverted to the compound of formula I-B in a simple and economicalmanner. By the process of this invention, the compound of formula I-Acan be directly converted to the compound of formula I-B in a simple andeconomic manner.

The first step of this invention is carried out by esterifying thecompound of formula I-A with a lower alkanol to form the compound offormula II. Any conventional method of esterifying an organic acid witha lower alkanol can be utilized to carry out this reaction. Among thepreferred methods for esterification is reacting the compound formulaI-A with a lower alkanol such as methanol in the presence of an organicacid such as p-toluene sulfonic acid. Generally, the lower alkanol canact as the solvent medium.

The compound of formula II is converted to the compound of formula IIIby treating the compound of formula II with an oxidizing agent. Anyconventional oxidizing agents can be utilized to carry out thisreaction. The oxidizing agents which are utilized can be anyconventional oxidizing agent which converts hydroquinone tobenzoquinones. Among the preferred oxidizing agents are included Ferricchloride, nitric acids, ceric sulfate, etc. Any of the conditionsconventional in utilizing these oxidizing agents can be utilized incarrying out this reaction.

The compound of formula III is converted to the compound of formula IVby treatment with a compound of the formula:

    R.sub.4 SO.sub.2 X                                         VIII

wherein R₄ is as above; and

X is halogen.

In the compound of formula VIII, R₄ can be any lower alkyl group. Thepreferred compound of formula VIII is methane sulfonyl chloride.

Generally the reaction of the compound of formula III with the compoundof formula VIII to produce a compound of the formula IV is carried outin the presence of an organic amine base. Any conventional organic aminebase can be utilized in carrying out this reaction. Among the preferredbases are included the tri(lower alkyl)amines and pyridine. Anyconventional tri(lower alkyl)amine can be utilized in carrying out thisreaction. Among the preferred amines are included methyl-diethyl amine,triethyl amine, trimethyl amine, etc. Generally, this reaction iscarried out in the presence of an inert organic solvent. Anyconventional inert organic solvent can be utilized. Among the preferredinert organic solvents are the halogenated hydrocarbons such asdichloromethane. In carrying out this reaction, temperatures from -20°C. to +10° C. are generally utilized.

The compound of formula IV is converted to the compound of formula V bytreating the compound of formula IV with a reducing agent and a base. Inaccordance with this invention, it has been discovered that this processoccurs with complete inversion of stereo configuration. This reactioncan be carried out by treating the compound of formula IV with areducing agent in the presence of a base. The reducing agent can be anyconventional quinone reducing agent. Any of the conventional reducingagents utilized to reduce quinones to hydroquinones can be utilized incarrying out the process of this invention. Among the preferred quinonereducing agents are included alkali metal hydrosulfites, alkalimetalborohydrides, or catalytic hydrogenation. Where an alkali metalborohydride is utilized, the preferred borohydrides are sodiumborohydride, potassium borohydride, and lithium borohydride. Thepreferred alkali metal hydrosulfites, are sodium and potassiumhydrosulfites. Among the preferred catalysts for use in catalytichydrogenation are palladium and platinum as well as the other metalswhich are conventionally used in catalytic hydrogenation. Thesecatalysts can be used alone or on conventional supports such as charcoalor carbon.

Any conventional base may be present in this reaction during thetreatment of the compound of formula IV with a reducing agent. On theother hand, the base can be utilized after the reduction has beencarried out. Any conventional base can be utilized in carrying out thisreaction. Among the preferred bases are the inorganic bases such as thealkali metal hydroxides as well as the organic bases such as the alkalimetal lower alkoxides, pyridine and the (lower alkyl)amines mentionedhereinbefore.

Generally, this reaction is carried out in a polar solvent. Among theconventional polar solvents are included lower alkanols, ethers such asdiethyl ether or tetrahydrofuran. Any conventional polar solvent can beutilized in carrying out this reaction. In carrying out this reaction,temperature and pressure are not critical and this reaction can becarried out at room temperature and atmospheric pressure. On the otherhand, elevated or reduced temperatures can be utilized. Generally, it ispreferred to carry out this reaction in a temperature of from 0° C. to70° C.

The compound of formula V is converted to the compound of formula I-B byhydrolysis. Any conventional method of ester hydrolysis can be utilizedto carry out this conversion.

The following examples are illustrative but not limitative of theclaimed invention. In the Examples, the ether is diethyl ether. In thefollowing examples, the "usual work-up" involves 3 extractions with thespecified solvent. The organic extracts were then washed with water andsaturated brine, dried over anhydrous magnesium sulfate, filtered andconcentrated at 40°-50° C. under water aspirator pressure. Residues weredried to constant weight under high vacuum. Unless otherwise noted,reactions were carried out under an atmosphere of argon. Columnchromatography was performed using silica gel.

EXAMPLE 1(R)-(+)-3,4-Dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-carboxylicAcid Methyl Ester

A solution of 2g(8 mmoles) of optically pure(R)-(+)-3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-carboxylicacid; [α]_(D) ²⁵ + 65.84° (c 1.18, C₂ H₅ OH) and 0.1g ofp-toluenesulfonic acid monohydrate in 40 ml of methanol was stirred andrefluxed for 3.75 hr. After cooling, the solution was diluted with waterand worked-up with ether in the usual manner (the ether extracts wereadditionally washed with saturated aqueous sodium bicarbonate solution)giving 2g (94.7%) of(R)-(+)-3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-carboxylicacid methyl ester as a colorless solid, mp 132°-134.5°; [α]_(D) ²⁵ +61.4° (c 4.91, CH₃ OH). The analytical specimen was obtained byrecrystallization of a sample from aqueous methanol as a colorlesssolid, mp 133.5°-135°; [α]_(D) ²⁵ + 61.85° (c 5.07, CH₃ OH).

EXAMPLE 2 (R)-(-)-Methyl2-Hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxo-1,4-cyclohexadien-1-yl)butanoate

To a stirred solution of 1.5g (5.68 mmoles) of(R)-(+)-3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-carboxylicacid methyl ester in 22 ml of ether, was added a solution of 4.5g (16.6mmoles) of ferric chloride hexahydrate in 17 ml of water and 17 ml ofmethanol. The addition was carried out in approximately 6 ml portions at0.5 hr intervals. One-half hour after the last addition, the ether layerwas separated and the aqueous phase was further worked-up by etherextraction in the usual manner. There was obtained 1.5g of a yellow oilwhich was chromatographed on 75g of silica gel. Elution with 9:1 partsby volume and 4:1 parts by volume toluene-ethyl acetate yielded 1.35g(84.9%) of (R)-(+)-methyl2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxo-1,4-cyclohexadien-1-yl)butanoate as a yellow oil; [α]_(D) ²⁵ -21.01° (C 0.96, CHCl₃).

EXAMPLE 3

A suspension of 2.64g (10 mmoles) of(R)-(+)-3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-carboxylicacid methyl ester ([α]_(D) ²⁵ + 61.00° (c 3.05, CH₃ OH) in 25 ml ofether was vigorously stirred with ice-bath cooling while 5 ml (80mmoles) of 70% by weight aqueous nitric acid was added dropwise over a15 min period. The resulting bright yellow solution was cautiouslypoured into excess saturated aqueous sodium bicarbonate solution.Work-up with ether in the usual manner gave 2,78g (99.5%) of(R)-(-)-methyl2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxo-1,4-cyclohexadien-1-yl)butanoate as a yellow oil. This material was identical with thatproduced as in Example 2 above.

EXAMPLE 4 (R)-(-)-Methyl2-Methyl-2-[(methylsulfonyl)oxyl-4-(2,4,5-trimethyl-3,6-dioxo-1,4-cyclohexadien-1-yl)butanoate

To a stirred solution of 0.74g (2.66 mmoles) (R)-(-)-methyl2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxo-1,4-cyclohexadien-1-yl)butanoatein 18 ml of dichloromethane, cooled in an ice-bath, was added 2.43 ml(1.77g; 17.5 mmoles) of triethylamine followed by 1.35 ml (2.01g; 17.5mmoles) of methanesulphonyl chloride. The mixture was kept at 0° for 64hr then treated with water. The dichloromethane solution was processedin the usual manner to give 1.45g of an oily product which waschormatographed on 75g of silica gel. Elution with 9:1 parts by volumetoluene-ethyl acetate afforded 0.69g (72.5%) of (R)-(-)-methyl2-methyl-2-[(methylsulfonyl)oxy]-4-(2,4,5-trimethyl-3,6-dioxo-1,4-cyclohexadien-1-yl)butanoate as a yellow solid. Recrystallization of asample from hexane-ethyl acetate provided yellow crystals, mp 112°-114°;[α]_(D) ²⁵ -5.24° (c 1.05, CHCl₃).

EXAMPLE 5 (S)-(+)-3,4-Dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-carboxylicAcid Methyl Ester

A slurry of 0.358g (1 mmole) of(R)-(-)-methyl-2-[(methylsulfonyloxy]-4-(2,4,5-trimethyl-3,6-dioxo-1,4-cyclohexadien-1-yl)butanoatein 5 ml of methanol was stirred rapidly, at room temperature, while asolution of 0.261g (1.5 mmoles) of sodium dithionite in 3 ml of 1Naqueous sodium hydroxide was added dropwise over a 5 min period. Theresulting mixture was stirred at room temperature for 20 min thenrefluxed for 5 min. After cooling, 20 ml of water was added and thecolorless slurry was filtered with suction. The solid was washed withwater then dried under high vacuum giving 0.246g (93.2%) of(S)-(-)-3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-carboxylicacid methyl ester as a colorless solid, mp 132.5°-135°; [α]_(D) ²⁵-60.62° (c 3.09, CH₃ OH). This material was homogeneous on TLC analysis.

EXAMPLE 6

A mixture of 1g (2.79mmoles) of (R)-(-)-methyl2-methyl-2-[(methylsulfonyl)oxyl-4-(2,4,5-trimethyl-3,6-dioxo-1,4-cyclohexadien-1-yl)butanoate,0.2g of 5% palladium on charcoal and 125 ml of methanol was stirred inan atmosphere of hydrogen until gas uptake ceased. The catalyst wasfiltered with suction on a pad of Celite and the filtrate wasimmediately treated with 8.3 ml (11.16 mmoles) of 1.34 M methanolicsodium methoxide. After stirring for 1 hr at room temperature, thesolution was acidified with 3 N aqueous hydrochloric acid and pouredinto saturated brine. Work-up with ether in the usual manner gave 0.638gof a tan solid which was chromatographed on 25g of silica gel. Elutionwith 19:1 parts by volume and 9:1 parts by volume toluene-ethyl acetatefurnished 0.491g (66.7%) of(S)-(-)-3,4-dihydro-6-hydroxy-2,5,6,8-tetramethyl-2H-1-benzopyran-2-carboxylicacid methyl ester as a colorless solid; [α]_(D) ²⁵ -59.93° (c 3.01, CH₃OH).

EXAMPLE 7

To a solution of 0.5g (1.4 mmoles) of (R)-(-)-methyl2-methyl-2-[(methylsulfonyl)oxy]-4-(2,4,5-trimethyl-3,6-dioxo-1,4-cyclohexadien-1-yl)butanoatein 30 ml of methanol, at room temperature, was added a solution of 20.2mg (0.53 mmole) of sodium borohydride in 10 ml of methanol, dropwise,with stirring. After stirring at room temperature for 50 min, 5.77 ml(7.73 mmoles) of 1.34 M methanolic sodium methoxide was added andstirring was continued for 2 hr, at room temperature. The resultingsolution was acidifed with 1 N aqueous hydrochloric acid then pouredinto saturated brine and worked-up with ether in the usual manner. Thecrude, crystalline product (0.34g) was chromatographed on 20g of silicagel. Elution with 19:1 parts by volume toluene-ethyl acetate gave 0.311g(84.1%) of(S)-(+)-3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-carboxylicacid methyl ester as a colorless solid, mp 131-134°; [α]_(D) ²⁵ -60.46°(c 3.88, CH₃ OH).

I claim:
 1. A compound of the formula ##STR4## wherein R₁, R₁ ' and R₁ "are hydrogen or lower alkyl, R₅ is --SO₂ R₆ ; R₆ is lower alkyl and R₂and R₃ are lower alkyl.
 2. The compound of claim 1 where said compoundis (R)-(+)-methyl2-methyl-2-[(methylsulfonyl)oxy]-4-(2,4,5-trimethyl-3,6-dioxo-1,4-cyclohexadien-1-yl)butanoate.